Molecular Vision 2021; 27:396-402
Asymptomatic retinal dysfunction in alpha-methylacyl-CoA racemase deficiency
Abrar K. Alsalamah,1,2 Arif O. Khan1,3
1Eye Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates; 2Vitreoretinal and Uveitis Divisions, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; 3Department of Ophthalmology, Cleveland Clinic Lerner College of Medicine of Case Western University, Cleveland, OH
Purpose: Alpha-methylacyl-CoA racemase (AMACR) deficiency is a peroxisomal disorder due to biallelic mutations in AMACR. At least 13 genetically confirmed patients have been reported to date. Seven had obvious pigmentary retinopa- thy; however, for the other six, no retinal phenotype was mentioned. The purpose of this report is to document subtle retinal findings in an additional affected family. Methods: Retrospective case series (three affected siblings and their unaffected parents). Results: Three Arab siblings (16, 19, and 22 years old) with prior juvenile cholelithiasis had been diagnosed with AMACR deficiency based on biochemical analysis, whole exome sequencing, and confirmatory segregation analysis (AMACR NM_001167595.1: c.877T>C; p.C293R). For all three, there were no visual complaints, but retinal multimodal imaging and electroretinography suggested subtle retinal dysfunction. Conclusions: Retinal dysfunction is a parameter that should be measured in patients with known or suspected AMACR deficiency even in the absence of visual symptoms. This may be helpful with clinical diagnosis and monitoring response to dietary interventions.
Peroxisomes are non-autonomous cellular organelles presentation (infancy or later adulthood) [4-14]. The clinical with important catabolic and metabolic functions, including spectrum includes neonatal cholestatic liver disease or giant lipid metabolism [1]. Peroxisomal alpha-oxidation breaks cell hepatitis or both, fat-soluble vitamin deficiency, bloody down phytanic acid, a dietary methyl-branched fatty acid stool in early life secondary to vitamin K deficiency [5,7], mainly derived from dairy products, meat, and certain fish learning difficulties [4,11], and neurologic disease, including [1]. This yields pristanic acid, which, in turn, is degraded by encephalopathic episodes, sensory and motor neuropathy, peroxisomal beta-oxidation [1]. Peroxisomal beta-oxidation seizures, and cerebellar signs [4,6,8-14]. Some patients also enables the synthesis of docosahexaenoic acid, an develop recurrent rhabdomyolysis and stroke-like episodes, omega-3 fatty acid enriched in neuronal tissue and photo- tremor, and hypogonadism [4,10,11]. receptor outer segments, and of bile acids [2]. Peroxisomal Of the 13 previously reported patients [4-14], seven were disorders can be broadly classified as disorders of peroxi- noted to have clinically obvious pigmentary retinopathy some biogenesis, such as Zellweger syndrome, and single [4,8,10,11,13,14]. However, for the other six [5-7,9,12], retinal peroxisomal enzyme deficiencies, such as alpha-methylacyl- appearance or function was not mentioned. Most of the previ- CoA racemase (AMACR) deficiency [3]. AMACR catalyzes ously reported patients with clinically obvious pigmentary conversion of certain compounds with a 2R-methyl branch, retinopathy did not have electrophysiology studies, and for the such as pristanic acid and bile acid intermediates, to their few who did the details were limited. In this report, we docu- S-stereoisomers, which is the form that is degradable by ment three additional siblings affected by this rare disorder peroxisomal beta-oxidation. Thus, patients with AMACR and highlight that such patients should be evaluated for retinal deficiency have markedly elevated levels of (2R)-pristanic dysfunction even if they do not have visual complaints. acid and of C27-bile acid intermediates. Phytanic acid can be mildly elevated as well. Thirteen patients with AMACR METHODS deficiency have been reported (11 genetically confirmed; four pathogenic variants), with hepatic and neurologic mani- A retrospective chart review for an affected family was festations the most prominent features and a bimodal age of performed. Institutional review board approval was granted for this retrospective case series. The study adhered to the tenets of the Declaration of Helsinki and ARVO statement Correspondence to: Arif O. Khan, Eye Institute, Cleveland Clinic on human subjects. Abu Dhabi, PO Box 112412, Abu Dhabi, United Arab Emirates, email: [email protected]
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RESULTS compliant. He was referred for ophthalmic examination although he had no visual complaints. His best-corrected The first three of five siblings born to first-cousin Emirati visual acuity was 20/20 in each eye (wearing his cycloplegic parents (Figure 1) were diagnosed with AMACR deficiency refraction of −1.50 + 1.00 × 096, −0.75 + 1.50 × 084). There based on biochemical analysis and whole exome sequencing were mild intermittent exotropia and red-green color defi- in one sibling (Sibling 1) with confirmatory targeted segrega- ciency with Ishihara color plate testing. Slit-lamp examina- tion analysis. Their main symptoms were learning difficul- tion was notable for rare fine white lens opacities in both ties and juvenile cholelithiasis. Other features of AMACR eyes that were not visually significant (Figure 2B). Retinal deficiency, such as sensorimotor neuropathy, cerebellar appearance and short-wave autofluorescence were unremark- dysfunction, and seizures, were not evident. The phenotype able (Figure 2A,C,F,H). Macular spectral-domain optical segregated with the novel homozygous AMACR (OMIM coherence tomography (SD-OCT) revealed subtle abnor- 604489; Gene ID 23600) variant NM_001167595.1: c.877T>C; malities (Figure 2D,E,G). ffERG showed normal waveforms p.C293R. All three siblings were confirmed as homozygous with mildly decreased photopic amplitudes (Table 1). pERG for the variant, and both parents, who did not have medical showed a decreased P50 amplitude (and thus, a decreased issues, were confirmed as carriers [15]. In addition to results downstream N95 amplitude; Figure 3A). This was consistent of segregation analysis and biochemical analysis (described with subnormal macular function [17]. below), the following also supports pathogenicity of this novel missense variant: the highly conserved nucleotide and Sibling 2 was a 19-year-old female with learning diffi- amino acid position, the large physiochemical differences culties and a history of juvenile cholelithiasis (initial presen- between cysteine and arginine, and prediction of the variant tation at 12 years old). The biochemical workup revealed as probably damaging by software analyses (PolyPhen-2 marked elevated pristanic acid levels and elevated liver [Polymorphism Phenotyping-2], SIFT [Sorting Intolerant enzymes. Targeted sequencing confirmed the homozygous From Tolerant], Align-GVGD [Align-Grantham Variation AMACR variant c.877T>C; p.C293R identified in her affected Grantham Difference]). Neither parent and none of the three brother (Sibling 1). She was placed on cholic acid, fat-soluble affected siblings had any visual complaints other than need vitamin supplements, and a low phytanic acid and pristanic for refractive correction. When asked specifically, none of acid diet but was poorly compliant. Her best-corrected visual the three siblings complained of nyctalopia, photophobia, or acuity was 20/20 in each eye (wearing her cycloplegic refrac- visual field constriction. Ophthalmic examination of both tion of −2.50). Ishihara color plate testing was normal. The parents revealed the mother had fine rare fine lens opacities, ophthalmic examination, retinal multimodal imaging, and which were not visually significant. Electrophysiology (full- ERG results were similar to those of her affected brother field electroretinography [ffERG] and pattern electroretinog- (Sibling 1). ffERG showed normal waveforms with mildly raphy [pERG]) was performed with the Diagnosys E3 desktop decreased photopic amplitudes (Table 1, Figure 4). pERG system using DTL electrodes and the manufacturer’s control showed a decreased P50 amplitude (and thus, a decreased database. Guidelines of the International Society for Clinical Electrophysiology of Vision were followed [16]. Mydriasis and compliance were as required during electrophysiology testing.
Sibling 1 was a 16-year-old male with learning difficul- ties and a history of infantile cholelithiasis (initial presen- tation at 2 years old). The biochemical workup revealed markedly elevated pristanic acid levels (9.29 μg/ml; normal <0.3 μg/ml), normal phytanic acid levels, elevated liver enzymes, the presence of 25R-trihydroxycholestanoic acid, and the absence of 25S-trihydroxycholestanoic acid. This biochemical profile strongly suggested AMACR deficiency, and whole exome sequencing confirmed the homozygous AMACR variant c.877T>C; p.C293R. Segregation analysis confirmed the parents to be heterozygous for the variant. He was placed on cholic acid, fat-soluble vitamin supplements, and a low phytanic acid and pristanic acid diet but was poorly Figure 1. Pedigree of the three affected siblings.
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Sibling 3 was a 22-year-old female with a history of learning difficulties and juvenile cholelithiasis (initial presen- DISCUSSION tation at 13 years old). The biochemical testing revealed mark- For these three siblings with AMACR deficiency, there were edly elevated pristanic acid levels, elevated liver enzymes, no visual complaints, and the clinical appearance of the retina and low fat-soluble vitamin levels. Targeted sequencing was normal. However, retinal multimodal imaging and elec- confirmed the homozygous AMACR variant c.877T>C; trophysiology revealed subtle abnormality of the central outer p.C293R identified in her affected brother (Sibling 1). During retinal layer and macular dysfunction, respectively. These the ophthalmic evaluation, her best-corrected visual acuity findings highlight that even in the absence of visual symp- was 20/20 in each eye (wearing her cycloplegic refraction of toms or clinically obvious pigmentary retinopathy, AMACR −1.25 + 0.25 × 090, −1.25 + 0.50 × 090). She had moderate- deficiency may cause retinal dysfunction, a parameter that angle intermittent exotropia. Ishihara color plate testing was can be objectively measured. We suspect the six patients normal. Ophthalmic examination and multimodal imaging previously reported with AMACR deficiency for whom were similar to that of her two siblings (Siblings 1 and 2). retinal findings were not mentioned [5-7,9,12] would have had ffERG showed normal waveforms with a decreased photopic signs of retinal dysfunction on multimodal imaging or retinal flicker amplitude in the left eye (Table 1). pERG showed a electrophysiology. Table 2 summarizes clinical features of the decreased P50 amplitude (and thus, a decreased downstream reported patients with AMACR deficiency.
Figure 2. Sibling 1. A: The appearance of the right eye retina is normal. B: The slit-lamp examination of the right eye shows fine white opacities; these were in both eyes and not visually significant. C: The appearance of the left eye retina is normal. D, E: Macular spectral- domain optical coherence tomography (SD-OCT) of the right and left eyes reveals subtle findings, which are shown with magnification in G: The hyporeflective band (outer segments; OS) normally seen in the parafoveal area between the hyper-reflective layers associated with the inner/outer segment junction (IS/OS) and the RPE/Bruch’s membrane (RPE/BM) complex is not seen; in addition, the RPE/BM layer has a blurred rather than a sharp appearance. F: Short-wave autofluorescence of the right eye is normal. G: Enlargement of right eye SD-OCT with control. H: Short-wave autofluorescence of the left eye is normal.
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Table 1. ERG values in the siblings.
Scotopic flash 0.01 Scotopic flash 3.0 Photopic flash Photopic flicker Sibling b-wave, implicit a-wave, implicit time; a-wave, implicit time; trough time; Interpretation time b-wave, implicit time b-wave, implicit time peak, time decreased phot- 12ms; Sibling 1 235uV, 96ms −134uV, 15ms; −14uV, 12ms; opic amplitudes 165mv, 50ms 50uV, 29ms 60uV, 25ms 235uV, 92ms −230uV, 15ms; −34uV, 15ms; 12ms; 324uV, 54ms −89uV, 29ms 69uV, 25ms −183uV, 15ms; 146uV, decreased phot- Sibling 2 259uV, 90ms −17uV, 12ms; 67uV, 30ms 12ms; 54uV, 26ms 53ms opic amplitudes −137uV, 15ms; 203uV, 149uV, 82ms −18uV, 14ms; 72uV, 30ms 12ms; 64uV, 26ms 49ms decreased −268uV, 16ms; 480uV, 14ms; 130uV, photopic flicker Sibling 3 385uV, 85ms −36uV, 15ms; 141uV, 30ms 56ms 27ms amplitude left eye −154uV, 16ms; 206uV, 88ms −24uV, 14ms; 105uV, 29ms 11ms; 91uV, 27ms 257uV,54ms −175.1±146.7uV, −64.17±38.03uV, 9.08±2.62ms; Normal 235.4±151.4uV, 16.73±5.15ms; 16.33±1.56ms; 191.2±82uV, range 95.82±22.12ms 230.1±273.2uV, 183.5±116.9uV, 27.5±3.13 24.17±4.33ms 46.09±11.78ms ms
The three affected siblings had visually insignificant lens acids with supplementation of cholic acid could potentially opacities. Although peroxisomal disorders can cause cata- limit retinal dystrophy as well as neuronal degeneration [1-4]. ract [1], the lens opacities in these three siblings were likely However, given the rarity of the disease, to date this has not unrelated to the AMACR deficiency. Visually insignificant been conclusively demonstrated. We suggest that multimodal lens opacities are often inherited as an autosomal dominant and electrophysiological monitoring of retinal function, even trait [18], and in this family, the mother had them as well. in individuals without overt pigmentary retinopathy, is a Similarly, the red-green color deficiency in the brother was potential method by which response to dietary modification likely the common form of color deficiency found in up to 8% could be assessed and monitored. of males and unrelated to AMACR deficiency.
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Articles are provided courtesy of Emory University and the Zhongshan Ophthalmic Center, Sun Yat-sen University, P.R. China. The print version of this article was created on 1 July 2021. This reflects all typographical corrections and errata to the article through that date. Details of any changes may be found in the online version of the article.
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